Is RIGI p.Val38Ala (c.113T>C) pathogenic?

RIGI p.Val38Ala (c.113T>C) is classified Uncertain significance in RIGI (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-03). AlphaMissense: likely benign (0.1545); Ultra-rare (popmax 0.0164%, mid).

How common is RIGI p.Val38Ala (c.113T>C) in the general population?

RIGI p.Val38Ala (c.113T>C) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about RIGI p.Val38Ala (c.113T>C)?

AlphaMissense predicts likely benign (score 0.1545) — an in-silico prediction, not a clinical call.

RIGI p.Val38Ala

c.113T>C · rs775318886 · VCV1419633

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1545 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1545	likely benign
REVEL	0.032	moderately benign-leaning
SaProt	LLR -8.31	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.22	acceptor loss, 3 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 7.1	GERP 1.4, phastCons 0.98
Regional constraint	o/e 1.04	unconstrained · MANE · 37 kb · p 0.5 · regional, not allelic
Overall
CADD	21.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.00062% 10/1,613,226 alleles · ultra-rare exomes 8/1,461,134 · genomes 2/152,092 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
Remaining individualsnot grpmax-eligible	0.0032%	31,227
Admixed American	0.00167%	59,776
European (non-Finnish)	0.000509%	196,641

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: RIGI
Protein: p.Val38Ala
Coding: c.113T>C
MANE Select: NM_014314
dbSNP: rs775318886
Type: single nucleotide variant
Location: chr9:32500933 (GRCh38)
Structure: AlphaFold pLDDT 85.40 · 44 PDB
Residue 38: the card 1 domain; an α-helix

Full RIGI gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RIGI p.Val38= Likely benign ★ same residue
RIGI c.1923+1G>A Uncertain significance ★★ same type
RIGI c.954-6T>G Uncertain significance ★★ same type
RIGI p.Ala436Val Uncertain significance ★★ ⚠ same type
RIGI p.Ala486Thr Uncertain significance ★★ ⚠ same type
RIGI p.Ala537Ser Uncertain significance ★★ ⚠ same type
RIGI p.Ala537Thr Uncertain significance ★★ ⚠ same type
RIGI p.Ala774Thr Uncertain significance ★★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/rigi-p-val38ala (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown